Linking metabolism to ageing: a new role for histone lysine acetylation

将新陈代谢与衰老联系起来：组蛋白赖氨酸乙酰化的新作用

• 批准号: BB/P00296X/1
• 负责人: Jane Mellor
• 金额: $ 83万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP00296X%2F1
• 关键词: Linking; metabolism; ageing; new; role

Healthy ageing is influenced by diet and light/dark cycles that control the interconnected metabolic and circadian cycles within cells. We study baker's yeast, which has a metabolic cycle and ages similarly to humans, providing a tractable system to discover the processes that coordinate cycles and ageing. Research aimed at discovering new ways of improving healthy ageing is rising to prominence, with work addressing the basic biology of ageing likely to underpin future medical advances. Much of our knowledge of the molecular processes involved in ageing has come from work using simple eukaryotes as model organisms. Furthermore, many of the genes and processes involved in ageing are conserved across evolution. We plan to investigate a new pathway linked to ageing at the fundamental level of gene expression, and the control of ageing by the metabolic state of the cell. In this project we will use a single-cell eukaryote, the yeast Saccharomyces cerevisiae. Yeast has many advantages for this work. We can synchronize yeast in their metabolic cycle meaning that we can study whole populations of cells with identical metabolic states. Yeast is one of the only systems in which it is possible to directly study the effect of metabolism on gene expression. Genes are packaged into chromatin, a complex of DNA and protein that influences gene expression. The chromatin is chemically modified in a reaction driven by the metabolic state of the cell, allowing gene expression and metabolism to be coordinated. It is generally believed that these chemical modifications influence the first step of gene expression, known as transcription, the copying of the genetic information in the DNA to the intermediate molecule RNA, which the then used as a template for the synthesis of proteins. We have discovered a new link between the chromatin and the last step of gene expression, the translation of the genetic information carried in RNA molecules into protein. This discovery was made possible by our ability to study particular regions of the chromatin that undergo chemical modifications in yeast, not possible in other organisms. This also enabled us to link this particular site of chemical modification on the chromatin to ageing in yeast. The purpose of this project is to understand how the chromatin influences translation of proteins and ageing. The characteristics of a cell, including how it ages, are controlled by proteins, in particular the amount of protein synthesized during translation. The production of proteins is central to cellular cycles and ageing, and is controlled by diet/nutrients, but the detailed processes are not understood. Defining these processes will contribute in the future to rational drug design aimed at alleviating symptoms of age-related conditions. Neurodegenerative conditions, for example, arise due to defects in the structures adopted by proteins, causing loss of normal function and cell death. The accumulation of defective proteins can be alleviated by altering how fast they are produced, and in yeast this leads to improved long-term viability of cells. In summary, we have discovered a novel nutrient-dependent target in chromatin that controls how fast proteins are produced and propose to dissect exactly how this is achieved. This work has important implications for understanding how diet and rhythmic cycles influence protein production and the molecular mechanisms behind age-related conditions.

健康的衰老受到饮食和控制细胞内相互关联的代谢和昼夜节律周期的光/暗周期的影响。我们研究了面包酵母，它有一个代谢周期和年龄类似于人类，提供了一个易于处理的系统来发现协调周期和衰老的过程。旨在发现改善健康老龄化的新方法的研究正在变得突出，解决老龄化的基本生物学的工作可能会支撑未来的医学进步。我们对衰老分子过程的认识，大部分来自于以简单的真核生物为模式生物的研究。此外，许多与衰老有关的基因和过程在进化过程中是保守的。我们计划在基因表达的基础水平上研究与衰老相关的新途径，以及细胞代谢状态对衰老的控制。在这个项目中，我们将使用单细胞真核生物，酵母酿酒酵母。酵母对这项工作有很多优势。我们可以同步酵母的代谢周期，这意味着我们可以研究具有相同代谢状态的整个细胞群。酵母是唯一可以直接研究代谢对基因表达影响的系统之一。基因被包装到染色质中，染色质是影响基因表达的DNA和蛋白质的复合物。染色质在细胞代谢状态驱动的反应中被化学修饰，从而使基因表达和代谢协调。一般认为，这些化学修饰影响基因表达的第一步，称为转录，将DNA中的遗传信息复制到中间分子RNA，然后将其用作蛋白质合成的模板。我们已经发现了染色质和基因表达的最后一步之间的新联系，即RNA分子中携带的遗传信息转化为蛋白质。这一发现是由于我们能够研究染色质的特定区域，这些区域在酵母中经历化学修饰，而在其他生物中是不可能的。这也使我们能够将染色质上的这个特定化学修饰位点与酵母的衰老联系起来。该项目的目的是了解染色质如何影响蛋白质的翻译和衰老。细胞的特征，包括它如何衰老，是由蛋白质控制的，特别是在翻译过程中合成的蛋白质的量。蛋白质的产生是细胞周期和衰老的核心，并受饮食/营养素的控制，但具体过程尚不清楚。定义这些过程将有助于在未来合理的药物设计，旨在减轻与年龄有关的疾病的症状。例如，神经退行性疾病是由于蛋白质结构缺陷引起的，导致正常功能丧失和细胞死亡。缺陷蛋白质的积累可以通过改变它们产生的速度来减轻，在酵母中，这导致细胞的长期生存能力提高。总之，我们在染色质中发现了一种新的营养依赖性靶点，它控制着蛋白质的产生速度，并提出了如何实现这一目标的具体方法。这项工作对于理解饮食和节律周期如何影响蛋白质产生以及年龄相关疾病背后的分子机制具有重要意义。

项目成果

Antisense transcription-dependent chromatin signature modulates sense transcription and transcript dynamics

反义转录依赖性染色质特征调节有义转录和转录动力学

• DOI: 10.1101/187237
• 发表时间: 2017
• 作者: Brown T

Mapping Human Transient Transcriptomes Using Single Nucleotide Resolution 4sU Sequencing (SNU-Seq)

• DOI: 10.1101/2021.07.14.452379
• 发表时间: 2021-07
• 期刊: bioRxiv
• 作者: Philipp Lorenz;Anna Lamstaes;Harry Fischl;S. Xi;Aksel J Saukko-Paavola;S. Murray;Thomas Brown;Charlotte L. George;A. Furger;Andrew Angel;J. Mellor

Paf1 Has Distinct Roles in Transcription Elongation and Differential Transcript Fate.

• DOI: 10.1016/j.molcel.2017.01.006
• 发表时间: 2017-02-16
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Fischl H;Howe FS;Furger A;Mellor J
• 通讯作者: Mellor J

Global and Gene-specific Transcriptional Responses to Acute Stress

对急性应激的整体和基因特异性转录反应

• DOI: 10.1101/2021.07.16.452657
• 发表时间: 2021
• 作者: Fischl H

Transcriptional changes are regulated by metabolic pathway dynamics but decoupled from protein levels

转录变化受代谢途径动力学调节，但与蛋白质水平脱钩

• DOI: 10.1101/833921
• 发表时间: 2019
• 作者: Feltham J